The present invention generally relates to the use of alpha-2 adrenergic receptor agents that are cleared from the anterior of an eye to treat an eye of a patient, and more specifically to ophthalmic compositions and drug delivery systems that provide extended release of the alpha-2 adrenergic receptor agents to an eye to which the agents are administered; and to methods of making and using such compositions and systems, for example, to treat or reduce one or more symptoms of an ocular condition to improve or maintain vision of a patient.
In ocular therapies, alpha agonists (e.g., agonists of alpha adrenergic receptors) are used to reduce aqueous humor production and increase aqueous humor outflow through the trabecular meshwork. The outflow through the trabecular meshwork accounts for about 90% of the eye's fluid drainage capability, and the remaining approximately 10% is provided by the uveoscleral outflow where fluid flows into the ciliar muscle beneath the trabecular meshwork. Two examples of alpha agonists used for ocular therapy include apraclonidine (IOPIDINE) and brimonidine-P (ALPHAGAN-P).
Brimonidine, 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline, is an alpha-2-selective adrenergic receptor agonist that is effective in the treatment of open-angle glaucoma by decreasing aqueous humor production and increasing uveoscleral outflow. Apraclonidine generally has, a mixed alpha-1 and alpha-2 stimulatory activity. Brimonidine is available in two chemical forms, brimonidine tartrate and brimonidine free base. Brimonidine tartrate (Alphagan® P) is publicly available by Allergan for treating glaucoma. Topical ocular brimonidine formulation, 0.15% Alphagan® P (Allergan, Irvine, Calif.), is currently commercially available for treatment of open-angle glaucoma. The solubility of brimonidine tartrate in water is, 34 mg/mL in water and 2.4 mg/mL in a pH 7.0 phosphate buffer while the solubility of brimonidine freebase is negligible in water.
Recent studies have suggested that brimonidine can promote survival of injured retinal ganglion nerve cells by activation of the alpha-2-adrenoceptor in the retina and/or optic nerve. For example, brimonidine can protect injured neurons from further damage in several models of ischemia and glaucoma.
Glaucoma-induced ganglion cell degeneration is one of the leading causes of blindness. This indicates that brimonidine can be utilized in a new therapeutic approach to glaucoma management in which neuroprotection and intraocular pressure reduction are valued outcomes of the therapeutic regimen. For brimonidine to protect the optic nerve, however, it must have access to the posterior segment of the eye at therapeutic levels. Currently available techniques for administering brimonidine to the posterior chamber of the eye are not sufficient to address this issue.
Agents that are administered to the vitreous of an eye of a patient can be eliminated from the vitreous by diffusion to the retro-zonular space (anterior clearance) with clearance via the aqueous humor, such as through the trabecular meshwork outflow and the uveoscleral outflow, or by trans-retinal elimination (posterior clearance). Most compounds that are relatively hydrophilic to moderately lipophilic utilize the former (anterior clearance) pathway unless a facilitated or active transport mechanism exists for these while extremely lipophilic compounds and those with trans-retinal transport mechanisms will utilize the latter (i.e., will go out through the retina). For example, macromolecules and peptides, including antibiotics, are often eliminated via the anterior route. In comparison, existing alpha 2 adrenergic receptor agonists are eliminated via the posterior route. This is most likely the result of an organic cationic transport mechanism in the outer blood retinal barrier, the RPE. Unfortunately, compounds that are eliminated across the retina have extremely short intravitreal half-lives. Additionally, these compounds tend to have extremely small aqueous humor/vitreous humor concentration ratios at steady-state. This dramatically impacts the treatment of anterior tissues from posterior administration of such compounds.
Intravitreal delivery of therapeutic agents can be achieved by injecting a liquid-containing composition into the vitreous, or by placing polymeric drug delivery systems, such as implants and microparticles, into the vitreous. Examples of biocompatible implants for placement in the eye have been disclosed in a number of patents, such as U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; and 6,699,493.
Other ocular therapies may include periocular delivery of drugs to a patient. Penetration of drugs directly into the posterior segment of the eye is restricted by the blood-retinal barriers. The blood-retinal barrier is anatomically separated into inner and outer blood barriers. Movement of solutes or drugs into the internal ocular structures from the periocular space is restricted by the retinal pigment epithelium (RPE), the outer blood-retinal barrier. The cells of this structure are joined by zonulae oclludentae intercellular junctions. The RPE is a tight ion transporting barrier that restricts paracellular transport of solutes across the RPE. The permeability of most compounds across the blood-retinal barriers is very low. Extremely lipophilic compounds, however, such as chloramphenical and benzyl penicillin, can penetrate the blood-retinal barrier achieving appreciable concentrations in the vitreous humor after systemic administration. The lipophilicity of the compound correlates with its rate of penetration and is consistent with passive cellular diffusion. The blood retinal barrier, however, is impermeable to polar or charged compounds in the absence of a transport mechanism. Hydrophilic to moderately lipophilic drugs can diffuse into the iris-ciliary body achieving very low posterior chamber or iris root concentrations. Anterior bulk flow of aqueous humor competes with the posterior elimination of drugs. For compounds that cannot passively penetrate the RPE, but are eliminated across the retina, it is extraordinarily difficult to achieve therapeutic concentrations of drugs at reasonable doses due to the differential rate processes involved.
Thus, there remains a need for new agents that can be used to treat ocular conditions, and that have different pharmacokinetic properties than existing agents.